This application claims priority of US provisional patent 61251769 filed on Oct. 15, 2009.
The cAMP-dependent protein kinase (PKA) is activated by the binding of cAMP to the regulatory subunit (R), of the molecule and results in the release of the active catalytic kinase subunit (C). Most of the effects of cAMP in eukaryotic systems are the result of phosphorylation of proteins at serine or threonine residues by PKA. There are several isoforms of both subunits of PKA. PKA is localized subcellularly by binding to multidomain scaffolding proteins known as AKAPs which bind to the R subunits of the holoenzyme [1]. More than 50 AKAPs are known which localize PKA in various cell types. The PKA-specific inhibitor (PKI) acts by binding with high affinity to the substrate binding site of the free active catalytic subunit [2].
Work done at the National Cancer Institute (NCI) and by others showed that the activity level of PKA is elevated in the plasma of cancer patients, and that anti-PKA antibody levels are elevated in the serum of cancer patients [3-6]. Humphries et al demonstrated that oxidation of PKA inhibited its activity [7]. This inhibition could be overcome by the addition of the reducing agent dithiothreitol. Unexpectedly, the current invention shows that activated (reduced) PKA activity is low in plasma or serum of cancer patients relative to that of controls.
PSA Screening Test for Prostate Cancer
The PSA (prostate-specific antigen) blood test for prostate cancer is of questionable value as a screening test. In fact the American Cancer Society no longer recommends that men routinely have PSA tests as part of their routine physical examinations [8]. There are several reasons for this lack of support for testing. When prostate cancer is present, the PSA test fails to detect 3 out of 4 cases [9]. In addition, when the PSA test comes back positive, 3 out 4 times it is a false positive—the patient does not have cancer [10]. Nonetheless, patients who have a positive PSA test typically will have a group of 12 or more biopsy samples taken from their prostate to verify if cancer is present. At an average cost of $1,500 per biopsy, the national cost for the 700,000 unnecessary prostate biopsies done each year exceeds $1 billion [11]. Making matters worse, there is a 25% chance that a prostate biopsy will not detect cancer even when cancer is present [12]. Improved patient outcome could be accomplished by replacing a biopsy with a cancer confirmatory blood test, for a savings in health care costs of nearly $900 million annually.
Mammogram Screening Test for Breast Cancer
Mammograms have a poorer record than PSA tests. While mammograms are purported to detect 85-90% of breast cancers when they are present, the detected tumors on average are 1½ inches in diameter when diagnosed. As for all cancers, earlier detection leads to better patient outcomes. What makes breast cancer screening costly is that an estimated 95% of the positive mammograms are false positives—the patient does not have cancer [13]. A positive mammogram frequently leads to a breast biopsy. A typical needle biopsy costs about $1,500; an invasive surgical biopsy (about ⅓ of all breast biopsies) costs about $5,000. This brings the national cost for the estimated 2 million unnecessary breast biopsies to more than $5.1 billion annually. Improved patient outcome could be accomplished by substituting a cancer confirmatory test for a biopsy, for a savings in health care costs of almost $5 billion annually.
Cancer Monitoring Tests
Beyond screening tests there are additional blood tests that are used to monitor cancer patients once cancer has been diagnosed. Many of these tests are not specific for cancer or specific for a particular type of cancer, rendering them useless as cancer screening tests. However, they can be an effective means for monitoring cancer treatment and testing for disease recurrence. These tests include CA-15.3 and CA27.29 for breast cancer, CA 125 for ovarian cancer, CEA for colon cancer and PSA for prostate cancer [14]. Other blood tests have been used to determine if a primary cancer has spread to other organs. These tests include assays for metastases to bone (osteoprotegrin), and liver (E-selectin).
Work done at the National Cancer Institute (NCI) and by others taught that the activity level of PKA is elevated in the plasma of cancer patients, and that anti-PKA antibody levels are elevated in the serum of cancer patients [3-4].